Cancer is the second leading cause of death in the world, after cardiovascular disease. Far from being optimistic, international agencies warn that the figures are increasing. In fact, according to projections of the World Health Organization, nearly 30 million new cases worldwide will be diagnosed in 2040, up 63.7% from today.
Given this forecasting, the pharmaceutical industry strives to discover new molecules for the treatment of the disease. PharmaMar is actively engaged in the cause and it is one of the ten Spanish pharmaceutical companies that the Ministry of Industry has recently qualified as excellent, taking into account industrial, economic and research & development and innovation aspects. In fact, this company already has two anti-tumor drugs, Yondelis and Aplidin, approved and marketed in different parts of the world and having been developed entirely in Spain.
In this new edition of ABGclients we interview Fernando García Chapinal, head of Industrial Property in PharmaMar. He tells us about the origin and history of the company and his work in the management of its intangible assets.
PharmaMar: from sea to lab
Can you briefly tell us the story of PharmaMar?
PharmaMar is a biopharmaceutical company focused on the search for new marine-derived compounds for cancer treatment. The company was founded in 1986 by Mr. José María Fernández Sousa-Faro.
How did the idea of searching marine compounds came to be?
The idea arises on the basis that, at that time, there were already enough natural products of terrestrial origin that had been developed and marketed for treating diseases, including cancer. However, the sea had not been explored for this purpose and we knew it contained the greatest biodiversity on our planet. 80% of all living beings are of marine origin and we thought this offered a unique opportunity for discovering new compounds with anti-tumor activity. Moreover, some studies indicate that about 1.8% of natural marine animal extracts may contain anticancer compounds.
Why focus on marine compounds?
Following this strategy PharmaMar has become the global leader in the field of oncology. We have reached important milestones as being the first company in the world to obtain approval of a drug of marine origin for the treatment of cancer. It happened in 2007 with Yondelis, a treatment for soft tissue sarcomas.
How are these marine compounds obtained?
In PharmaMar, our expeditions of divers collect marine extracts from all the seas of the world. They are then shipped to our Colmenar Viejo facilities perfectly refrigerated to ensure their conservation.
We use the extracts to do in vitro primary screening assays against a tumor cell panel looking for antitumor activity. When it occurs, our Natural Products Chemistry team identifies and elucidates the structure of the molecule with biological activity, what we call the active ingredient.
Then our Synthetic Chemistry team begins to work on the development of a synthetic process. It ensures the large-scale production of the molecule, minimizing the impact of industrial exploitation of the marine environment. In this way, we obtain sufficient amounts of active substance to initiate preclinical research.
Which specialties of science involve your projects?
We cover a good part of the specialties of science. Our team is composed by chemists, biochemists, pharmacists, biologists, oncologists, veterinarians, chemical engineers, etc. All of them are necessary to discover active molecules, do preclinical and clinical studies, and manufacture drugs under rigorous quality controls. In fact, there are 53 doctors (PhD) working with us, which reflects the company’s commitment to our own research.
PharmaMar new milestone: lurbinectedin under the accelerated approval procedure in the US
In addition to Yondelis, lurbinectedine is creating the biggest expectations for the company. Could you tell our readers what is the origin of the project?
Lurbinectedine is the result of the Medicinal Chemistry program that PharmaMar’s R&D team carried out in order to develop a second generation of the drug Yondelis. As a sign of the expectations created, it is noteworthy that lurbinectedin has already been designated an orphan drug for the treatment of small cell lung cancer by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Swiss Agency for Therapeutic Products and the Australian Therapeutic Goods Administration.
In recent months, lurbinectedine has achieved the company’s greatest milestones and has placed PharmaMar in the focus of current scientific development. The results of the Phase II “Basket” trial with lurbinectedin for the treatment of small cell lung cancer in monotherapy were reported at an oral presentation at the 2019 ASCO World Conference (American Society of Clinical Oncology).
Before its commercialisation, you need approval from the relevant medicines agency. In this sense, at what stage is lurbinectedine?
In December 2019, with the results of the aforementioned study, we applied for registering lurbinectedin under the FDA’s Accelerated Approval Program. FDA accelerated approvals are made with drugs for serious diseases without treatment, such as recurrent microcytic lung cancer.
Recently, the FDA has expedited the “Priority Review” for lurbinectedin. The “Priority Review” designation shortens the evaluation of the application for registration to 6 months, with all that implies, and speeds up the drug approval process. A standard process would take at least 10 months. This is another great news for the company. We already have a deadline for possible approval, FDA will issues its decision on lurbinectedin in the U.S. for microcytic lung cancer treatment before 16 August 2020. In case of being approved, lurbinectedin could start being commercialized in the second half of 2020.
Last December you signed an exclusive license agreement for lurbinectedine in the US with Jazz Pharmaceuticals. On what terms?
The agreement with Jazz Pharmaceuticals has become the largest in the company’s history. It could reach a total value of more than $1 billion. We have already received 200 million euros and the additional 800 are linked to regulatory milestones and business goals.
Besides the US, at what stage is lurbinectedin in other regions?
We are intensively working on the development of the drug and preparation of the registration dossier in other regions. In fact, we have licensing agreements with other partners in countries like Australia, New Zealand, South Korea, China, Vietnam, Malaysia and a few more Asian countries.
We hope to be able to deliver the drug to patients in these regions in the medium term, as well as many more in the rest of the world, such as Europe or Japan. By now, patients from 13 European countries and the rest of the world have already been treated with lurbinectedin under compassionate use.
The protection of Industrial Property in a pharmaceutical company
As PharmaMar’s Industrial and Intellectual Property Manager, what is your job?
Broadly speaking, my work as head of the Industrial Property area -which is part of the R&D Department- is to define the strategy of protecting the various assets and scientific developments of the company according to the general management criteria; to manage the patents and trademarks portfolio, which includes conducting regular audits of patents, as well as overseeing the drafting and prosecution of patent applications; to control what it is published to avoid harmful disclosures; to review the industrial property clauses of the company’s different agreements; and, finally, to monitor third-party publications and patents relating to our products.
PharmaMar has a broad portfolio of patents and applications, can you give us some figures? How is it managed?
The company’s patent portfolio is composed of around 1400 patents included in some 40 families. The intellectual property management model is integrated into the company’s business strategy. That is why we carry out periodic evaluations of the patent portfolio, maintaining only those families that we believe bring some value to the company.
Those ones either protect products in the development phase, or products that we are already commercializing ourselves or through our partners, or they constitute potential license assets to other companies. The latter case, for example, has happened with the Seattle Genetics company, which is specialized in the development and commercialisation of conjugated antibodies, and to which we have licensed several of our patents for use in this field.
What defines the geographical scope of patent protection?
The geographical scope of protection will depend on the interest in the project. Before making a decision and incurring a higher economic expense, we review the state of development of the project.
In any case, there are countries or regions where we are almost always seeking protection, including Europe, the United States, Japan, Australia, Canada and the BRICS countries. This represents more than 90% of the global pharmaceutical market. When the project is of greatest interest, we expand coverage to other regions such as South America, Southeast Asia, Arab States, etc…
In general there is the (wrong) belief that there is only one patent that protects a pharmaceutical product. What are the different levels of protection?
Once we have indications of in vivo efficacy of the drug with a tolerable toxicity level, we proceed to request protection for the molecule and analogues of it, in order to block potential competitors, as well as the synthetic method to obtain such compounds.
Later, usually during the first phase of clinical development, it is usual to try to seek protection for the pharmaceutical formulation of the active substance that is administered to patients, as well as dosages and regimes of administration of the drug.
Seeking protection of the use of the active substance in combination with another anti-tumor compound is also common. We apply for it when it is observed that the two substances, acting together, cause a greater response to the sum of the effects they would cause separately, what we call synergy.
Finally, any improvement in the original synthetic process of the active substance, as well as the discovery of some crystalline form during galenic development are susceptible to protection. All of this is not obvious and requires great R&D efforts.
Why is it important to have multiple levels of protection?
Keep in mind that the development of a new drug is a long process – usually between ten and fifteen years from the discovery to the release of the drug on the market -. It is also very expensive, so we try to maximize the time of patent protection. The goal is to protect the different R&D results during the development process to gain a monopoly on the resulting innovations, and thus try to recover investment and make a profit.
On the other hand, after the authorization of commercialisation of a drug, some regulatory administrations provide data exclusivity protection. This occurs, for example, in Europe, where generic companies are not allowed to commercialise the drug for a period of ten years. In Europe there is also the supplementary protection certificate that gives 5 additional years for the basic patent
In short, it would be a matter of having some form of patent protection for the medicament that would help maintain market exclusivity against companies of generics.
R&D: The key to PharmaMar
PharmaMar has many collaborations with research centers and universities. What role does IP play in these partnerships and how do you manage it?
That’s right, we have many collaborations with research centers, universities and hospitals, national and international. Each of them has its own IP policies and sometimes it is not easy to reach agreements.
We have a company policy that implies that any industrial property generated from the use of our compounds in any research carried out by the centers must belong to PharmaMar, because we are the ones who fund the research. Centers do not usually present problems and comply with the obligation to assign the inventions to PharmaMar, while we grant the right of publication to the authors.
It’s not like that in America. How do you manage it there?
In the United States, by law, inventions arising from federally funded research must belong to the government or the research center, and the situation is more complicated. It is usually solved by granting exclusive licenses by the centers. When negotiating research contracts, we must also take into account IP obligations with our partners in the licensing agreements for the development and commercialisation of our products, Yondelis, Aplidin or Lurbinectedin.
What difficulties does an innovative Spanish company focused on oncology like yours? (e.g. compared to American, or multinational companies)
In a sector as regulated as the pharmaceutical, where the development and approval times for a drug are quite long and very expensive, one of the main difficulties for a company like ours is to obtain funding in order to be able to undertake all these research projects.
We are currently making a great effort in R&D, dedicating 70% of our turnover to research. In this sense, our main source of income is from Yondelis’ sales for the treatment of soft tissue sarcoma (STS) and for ovarian cancer. It is already commercialised in about 80 countries. Sometimes we have also raised capital at the stock market.
A bigger support for R&D by the administration would also be desirable. We firmly believe that investing in research is investing in the future and in improving the patients’ quality of life.